The HPV vaccine is routinely recommended for girls 11 and 12 years of age and is given in a series of three injections over a six-month period. The second and third doses should be given two and six months (respectively) after the first dose.
The vaccine is also recommended for girls and women 13 through 26 years of age who did not receive it when they were younger. HPV vaccine may be given at the same time as other vaccines.
What is the HPV vaccine?
The vaccine, Gardasil, is the first vaccine developed to prevent cervical cancer, precancerous genital lesions, and Genital Warts due to HPV.
CDC recommends the HPV vaccine for all 11 and 12 year old girls. The recommendation allows for vaccination to begin at age nine. Vaccination also is recommended for females aged 13 through 26 years who have not been previously vaccinated or who have not completed the full series of shots.
Another HPV vaccine (being developed by GlaxoSmithKline) is in the final stages of clinical testing, but it is not yet licensed. This vaccine would protect against the two types of HPV that cause most cervical cancers.
The vaccine is given in a series of three injections over a six-month period. The second and third doses should be given at two and six months (respectively) after the first dose. HPV vaccine may be given at the same time as other vaccines.
This vaccine is highly effective in preventing four types of HPV in young women who have not been previously exposed to HPV. This vaccine targets HPV types that cause up to 70% of all cervical cancers and about 90% of Genital Warts. The vaccine will not treat existing HPV infections or their complications.
The FDA has licensed the vaccine as safe and effective. This vaccine has been tested in thousands of females (9 to 26 years of age) around the world. These studies have shown no serious side effects. The most common side effect is brief soreness at the injection site. CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use.
No, there is no thimerosal or mercury in the vaccine.
The length of vaccine protection (immunity) is usually not known when a vaccine is first introduced. So far, studies have found that vaccinated persons are protected for five years. More research is being done to find out how long protection will last, and if a booster dose of vaccine will be needed.
Will girls/women be protected against HPV and related diseases, even if they don’t get all three doses?
It is not yet known how much protection girls/women would get from receiving only one or two doses of the vaccine. For this reason, it is very important that girls/women get all three doses of the vaccine..
If a woman turns 27 years of age after the first dose of HPV was administered but before the third doses is administered, should the series be completed?
Yes, the series should be completed using the recommended intervals between doses, even if this means that the series is completed after a woman turns 27 years of age.
Yes, HPV vaccine is the first vaccine developed to prevent cervical cancer. This new vaccine is highly effective in preventing HPV infection, the major cause of cervical cancer in women. The vaccine protects against four types of HPV, including two that cause about 70% of cervical cancer.
The American Cancer Society estimates that in 2007, over 11,000 women will be diagnosed with cervical cancer and approximately 3,600 women will die from this disease.
Yes, they will still need to see their healthcare provider for cervical cancer screening. There are three reasons why women will still need regular cervical cancer screening. First, the vaccine will NOT provide protection against all types of HPV that cause cervical cancer, so women will still be at risk for some cancers. Second, some women may not get all required doses of the vaccine (or they may not get them at the right times), so they may not get the vaccine’s full benefits. Third, women may also not get the vaccine’s full benefits if they have already acquired a vaccine HPV type.
The vaccine has been extensively tested in 9 through 26 year-old females so information is only available about vaccine safety and protection for girls/women of this age group. However, studies on the vaccine are now being done in boys/men, as well as in women older than 26 years of age. The FDA will consider licensing the vaccine for these other groups when there is research to show that it is safe and effective in these groups.
It is important for girls to get HPV vaccine before they become sexually active. The vaccine is most effective for girls/women who get vaccinated before their first sexual contact. It does not work as well for those who were exposed to the virus before getting the vaccine. However, most women will still benefit from getting the vaccine because they will be protected against other virus types contained in the vaccine.
The vaccine is not recommended for pregnant women. There has only been limited information about vaccine safety among pregnant women and their unborn babies. So far, studies suggest that the vaccine has not caused health problems during pregnancy, nor has it caused health problems for the child. But more research is still needed. For now, pregnant women should wait to complete their pregnancy before getting the vaccine. If a women finds out she is pregnant after she has started getting the vaccine series, she should wait until after her pregnancy is completed to finish the three-dose series.
We do not yet know if the vaccine is effective in boys or men. Studies are now being done to find out if the vaccine works to prevent HPV infection and disease in males. When more information is available, this vaccine may be licensed and recommended for boys/men as well.
There are no federal laws requiring the immunization of children. All school and daycare entry laws are state laws and vary from state to state. Therefore, you should check with your state health department of Board of Education to find out what vaccines your child will need to enter school or daycare.
Each year the CDC publishes childhood and adolescent immunization schedules that provide recommended timelines for immunization of children and adolescents. The annual childhood and adolescent immunization schedules are a joint effort of the CDC, the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). While these organizations have no regulatory authority over the immunization of children, the recommendations of the CDC, AAP, and AAFP are considered standards of medical practice and most physicians follow the recommendations.
The retail price of the vaccine is $120 per dose ($360 for full series).
Most insurance plans and managed care plans cover recommended vaccines. However, there may be a lag-time after a vaccine is recommended, before it is available and covered by health plans. While some insurance companies may cover the vaccine, others may not.
The Vaccines for Children (VFC) program helps families of children who may not otherwise have access to vaccines by providing free vaccines to doctors who serve them. The VFC program provides free vaccines to children and adolescents younger than 19 years of age, who are either Medicaid-eligible, American Indian, or Alaska Native or uninsured. There are over 45,000 sites that provide VFC vaccines, including hospital, private, and public clinics. The VFC Program also allows children and adolescents to get VFC vaccines through Federally Qualified Health Centers or Rural Health Centers, if their private health insurance does not cover vaccinations. For more information about the VFC, visit www.cdc.gov/vaccines/programs/vfc/
Some states also provide free or low-cost vaccines at public health department clinics to people without health insurance coverage for vaccines.
HPV (human papillomavirus) is a virus that is common in the United States and around the world and can cause cancer and Genital Warts. HPV is spread through sexual contact. There are about 40 types of genital HPV. HPV is the major cause cervical cancer in women and is also associated with several other types of cancer in both men and women.
HPV is the most common sexually transmitted infection in the United States. At least 50 percent of sexually active people will get HPV at some time in their lives. Every year in the U.S., about 6.2 million people get HPV. HPV is most common in young women and men who are in their late teens and early 20s.
No, HPV is not the same as HIV or herpes virus (herpes simplex virus or HSV). While these are all viruses that can be sexually transmitted— HIV and HSV do not cause the same symptoms or health problems as HPV.
There is no cure for HPV. But there are treatments for the health problems that HPV can cause, such as genital warts, cervical cell changes, and cancers caused by HPV.
The government has developed a simple model to estimate the cost-effectiveness of HPV vaccination in the context of current cervical cancer screening in the United States. We found that the cost per QALY gained by adding routine vaccination of 12-year-old girls to existing screening practices ranged from $3,906 to $14,723 under base-case parameter values (depending on the model version we applied) and ranged from <$0 (cost-saving) to $122,976 in the sensitivity analyses when several key parameter values were varied. Our results were consistent with results of published studies based on more complex models, particularly when key assumptions (e.g., vaccine duration, efficacy, and cost) were similar.
The simplicity of the approach offers advantages and disadvantages. The main advantage is that it requires substantially fewer assumptions than the more complex Markov and transmission models. For example, there is no need to model the probability of HPV acquisition, the possible progression from HPV infection to disease, the mixing of sex partners, the probability of HPV transmission, and so forth. There also is no need to model cervical cancer screening and sexually transmitted disease prevention activities because these activities are reflected in the incidence rates of HPV-related health outcomes that we applied.
Because we do not model cervical cancer screening directly, however, we are unable to use our model to examine how changes in cervical cancer–screening strategies can affect the cost-effectiveness of HPV vaccination, and vice versa. For example, HPV vaccination is expected to reduce the positive predictive value of abnormal Papanicolaou (Pap) test results (38). However, our analysis did not include the loss in quality of life attributable to the initial distress associated with receiving an abnormal Pap result (39), regardless of whether it is a false positive. This omission of the lost QALYs due to abnormal Pap test results underestimates the benefits of HPV vaccination because vaccination is expected to offer moderate reductions in the number of abnormal Pap results overall (38,40). Future changes in screening strategies, such as delayed screening, could also possibly improve the cost-effectiveness of HPV vaccination .
Another disadvantage of our approach is that it offers only a rough approximation of the cost-effectiveness of HPV vaccination and is not suitable for examining strategies such as vaccination of boys and men. In addition, although many of the parameter values and assumptions in our model can be modified with ease, changing the assumption of lifelong duration of protection or examining vaccination at older ages would require the incorporation of assumptions about the incidence and natural history of HPV to account for the probability of acquiring HPV (before vaccination or after vaccine immunity wanes) and the subsequent probability of adverse HPV-attributable health outcomes. However, we can address the issue of waning immunity by assigning a higher cost per vaccination series (as in the sensitivity analyses) to reflect the cost of a booster.
Another limitation of our approach is the uncertainty in the key parameter values, such as the cost and loss in quality of life associated with HPV-related health outcomes, the percentage of health outcomes attributable to each type of HPV targeted by the vaccine, and the incidence of CIN and Genital Warts. However, our results were fairly robust in response to changes in these key parameter values. For example, when simultaneously varying the costs of HPV-related health outcomes and the loss in QALYs associated with HPV-related health outcomes, we found that the estimated cost per QALY gained by vaccination ranged from $3,262 to $21,779.
Our adjustments for the effect of herd immunity were arbitrary; we simply assumed an additional effect of vaccination in the nonvaccinated population. However, our results did not vary substantially (in absolute terms) when the assumed effect of herd immunity was varied. For example, the estimated cost per QALY gained by quadrivalent vaccination (including herd immunity and excluding the benefits of preventing cancers other than cervical) was $5,336 in the base case and ranged from $3,423 to $7,596 when the adjustments for the effects of herd immunity (including the impact on Genital Warts in males) were varied. We also note that the benefits to nonvaccinated persons were assumed to occur only in nonvaccinated persons of similar ages to those vaccinated. This restriction may have understated the potential benefits of herd immunity.
Our analysis did not address all of the potential costs and benefits of vaccination. For example, the cost-effectiveness estimates would have been more favorable to vaccination if we had included the potential for cross-protection against high-risk HPV types besides 16 and 18 ; the prevention of anal, vaginal, and vulvar cancer precursor lesions ; the prevention of other cancers not included in this analysis (such as anal cancer and oropharyngeal cancers in male patients); and the prevention of other HPV-related health outcomes such as recurrent respiratory papillomatosis. Conversely, the cost-effectiveness estimates would have been less favorable to vaccination if we had included the potential for HPV type replacement (i.e., an increase in HPV types not protected against by vaccination), waning immunity, and the possible costs and loss in quality of life associated with adverse side effects of vaccination.
A key finding from this analysis was that the choice of discount rate and time horizon has a substantial influence on the estimated cost-effectiveness of vaccination. Because the costs of HPV vaccination begin to accrue immediately but the full benefits of vaccination are not realized for many years, the cost-effectiveness of vaccination becomes less favorable when higher discount rates are applied or when shorter time horizons are examined.
Another key finding was that the potential benefits of preventing anal, vaginal, vulvar, and oropharyngeal cancers offer nontrivial improvements in the estimated cost-effectiveness of HPV vaccination. The inclusion of these additional benefits decreased the cost per QALY gained by vaccination by ?$2,200 (or 21%) in the population model (without herd immunity), by ?$1,400 (or 27%) in the population model (with herd immunity), and by ?$2,200 (or 25%) in the cohort model. Future studies that develop better estimates of the cost and loss in quality of life associated with these cancers could more accurately estimate the effects of these additional benefits on the cost-effectiveness of HPV vaccination. Despite the limitations discussed above, our simplified model provides useful estimates of cost-effectiveness of HPV vaccination in the United States. Our results were consistent with previous studies based on more complex models. This consistency is reassuring because models of various degrees of complexity will be essential tools for policy makers in the development of optimal HPV vaccination strategies.
HPV Vaccine Information For Young Women
There is now a vaccine that prevents the types of genital human papillomavirus (HPV) that cause most cases of cervical cancer and Genital Warts. The vaccine, Gardasil®, is given in three shots over six-months. The vaccine is routinely recommended for 11 and 12 year old girls. It is also recommended for girls and women age 13 through 26 who have not yet been vaccinated or completed the vaccine series.
Why the HPV vaccine is important
Genital HPV is a common virus that is passed on through genital contact, most often during sex. Most sexually active people will get HPV at some time in their lives, though most will never even know it. It is most common in people in their late teens and early 20s.
There are about 40 types of HPV that can infect the genital areas of men and women. Most HPV types cause no symptoms and go away on their own. But some types can cause cervical cancer in women and other less common genital cancers— like cancers of the anus, vagina, and vulva (area around the opening of the vagina). Other types of HPV can cause warts in the genital areas of men and women, called Genital Warts. Genital Warts are not a life-threatening disease. But they can cause emotional stress and their treatment can be very uncomfortable.
Every year, about 12,000 women are diagnosed with cervical cancer and almost 4,000 women die from this disease in the U.S.
About 1% of sexually active adults in the U.S. (or 1 million people) have visible genital warts at any point in time.
Who should get the HPV vaccine
The HPV vaccine is recommended for 11 and 12 year-old girls.1 It is also recommended for girls and women age 13 through 26 years of age who have not yet been vaccinated or completed the vaccine series.
1 Note: The vaccine can also be given to girls 9 or 10 years of age.
Will sexually active females benefit from the vaccine?
Ideally females should get the vaccine before they become sexually active, when they may be exposed to HPV. Females who are sexually active may also benefit from the vaccine, but they may get less benefit from it. This is because they may have already gotten an HPV type targeted by the vaccine. Few sexually active young women are infected with all HPV types covered by the vaccine so they would still get protection from those types they have not yet gotten. Currently, there is no test available to tell if a girl/woman has had HPV in the past, or which types.
Can pregnant women get the vaccine?
The vaccine is not recommended for pregnant women. There has been limited research looking at vaccine safety for pregnant women and their unborn babies. So far, studies suggest that the vaccine does not cause health problems for pregnant women or their developing child. But more research is still needed. For now, pregnant women should wait until their pregnancy is over before getting the vaccine. If a woman finds out she is pregnant after she has started getting the vaccine series, she should wait until her pregnancy is over before finishing the three-dose series.
Should girls/women be screened for cervical cancer before getting vaccinated?
No. Girls/women do not need to get an HPV test or Pap test to find out if they should get the vaccine. Neither of these tests can tell the specific HPV type(s) that a woman has (or has had in the past), so there’s no way to know if she has already had the HPV types covered by the vaccine.
Why is the HPV vaccine only recommended for girls/women through age 26?
The vaccine has been widely tested in girls/women 9 through 26 years of age. New research is being done on the vaccine’s safety and efficacy in women older than 26 years of age. The FDA will consider licensing the vaccine for these women when there is enough research to show that it is safe and effective for them.
What about vaccinating boys and men?
We do not yet know if the vaccine is effective in boys or men. It is possible that vaccinating males will have health benefits for them by preventing genital warts and rare cancers, such as penile and anal cancer. It is also possible that vaccinating boys/men will have indirect health benefits for girls/women. Studies are now being done to find out if the vaccine works to prevent HPV infection and disease in males. When more information is available, this vaccine may be licensed and recommended for boys/men as well.
Effectiveness of the HPV Vaccine
This vaccine targets the types of HPV that most commonly cause cervical cancer and genital warts. The vaccine is highly effective in preventing those types of HPV and related diseases in young women.
The vaccine is less effective in preventing HPV-related disease in young women who have already been exposed to one or more HPV types. That is because the vaccine does not treat existing HPV infections or the diseases they may cause. It can only prevent HPV before a person gets it.
How long does vaccine protection last? Will a booster shot be needed?
Research suggests that vaccine protection will last a long time. More research is being done to find out if women will need a booster vaccine many years after getting vaccinated to boost protection.
What does the vaccine not protect against?
The vaccine does not protect against all types of HPV— so it will not prevent all cases of cervical cancer. About 30% of cervical cancers will not be prevented by the vaccine, so it will be important for women to continue getting screened for cervical cancer (regular Pap tests). Also, the vaccine does not prevent other sexually transmitted infections (STIs). So it will still be important for sexually active persons to lower their risk for other STIs.
Will girls/women be protected against HPV and related diseases, even if they don’t get all three doses?
It is not yet known how much protection girls/women would get from receiving only one or two doses of the vaccine. For this reason, it is very important that girls/women get all three doses of the vaccine.
This vaccine has been licensed by the FDA and approved by CDC as safe and effective. It was studied in thousands of females (ages 9 through 26 years) around the world and its safety continues to be monitored by CDC and the FDA. Studies have found no serious side effects. The most common side effect is soreness in the arm (where the shot is given). There have recently been some reports of fainting in teens after they got the vaccine. For this reason, it is recommended that patients wait in their doctor’s office for 15 minutes after getting the vaccine.
The retail price of the vaccine is about $125 per dose ($375 for full series).
Is the HPV vaccine covered by insurance plans?
While some insurance companies may cover the vaccine, others may not. Most large insurance plans usually cover the costs of recommended vaccines.
How can I get help paying for the vaccine?
Children age 18 and younger may be eligible to get vaccines, including the HPV vaccine, for free through the Vaccines for Children (VFC) program if they are: Medicaid eligible; uninsured; or American Indian or Alaska Native. Doctors may charge a small fee to give each shot. However VFC vaccines cannot be denied to an eligible child if the family cannot afford the fee.
Some states also provide free or low-cost vaccines at public health department clinics to people without health insurance coverage for vaccines. Contact your State Health Department to see if your state has such a program.
What vaccinated girls/women need to know
Women will still need regular cervical cancer screening (Pap tests) because the vaccine will NOT protect against all HPV types that cause cervical cancer. Also, women who got the vaccine after becoming sexually active may not get the full benefit of the vaccine if they had already acquired HPV.
Other ways to prevent HPV and Cervical Cancer
Another HPV vaccine is now being considered for licensure by the FDA. This vaccine would protect against the types of HPV that cause most cervical cancers, but it would not protect against genital warts.
Are there other ways to prevent cervical cancer?
Regular cervical cancer screening and follow-up can prevent most cases of cervical cancer. The Pap test can detect cell changes in the cervix before they turn into cancer. Pap tests can also detect most, but not all, cervical cancers at an early, treatable stage. Most women diagnosed with cervical cancer in the U.S. have either never had a Pap test, or have not had a Pap test in the last 5 years. The HPV test can tell if a woman has HPV on her cervix. This test can be used with the Pap test to help your doctor determine next steps in cervical cancer screening.
Are there other ways to prevent HPV?
The only sure way to prevent HPV is to abstain from all sexual activity. For those who are sexually active, condoms may lower the chances of getting HPV, if used all the time and the right way. Condoms may also lower the risk of developing HPV-related diseases (genital warts and cervical cancer). But HPV can infect areas that are not covered by a condom—so condoms may not fully protect against HPV.
Sexually active adults can also lower their risk of HPV by being in a mutually faithful relationship with someone who has had no or few sex partners, or by limiting their number of sex partners. The fewer partners a person has had – the less likely he or she is to have HPV. But even persons with only one lifetime sex partner can get HPV, if their partner has had previous partners.
If you have already got HPV try the natural remedy of Herpeset which reliefs the Herpes symptoms.
The purpose of this document is to discuss the advantages and drawbacks of endpoints proposed for clinical efficacy trials to evaluate preventive HPV vaccines containing “oncogenic” HPV types. The ultimate goal for these vaccines is the prevention of cervical cancer. Since infection with an oncogenic HPV type is thought to be a necessary step in the pathogenesis of most cervical cancer, a number of potential endpoints proceeding from the initial infection are considered.
Endpoints in clinical studies may be defined as measurable outcome variables following an experimental intervention. Primary efficacy endpoints are usually selected to provide an outcome measure of the greatest clinical relevance. In efficacy trials of vaccines, prevention of a disease is commonly used as the primary outcome variable. However, the severity and stages of disease can vary considerably, and endpoints based on preventing disease of greater or lesser severity may be appropriate for vaccine efficacy trials.
Certain federal regulations relate to selection of efficacy endpoints. Under 21 CFR 314.125, FDA may refuse to approve a drug application if there is a lack of substantial evidence of efficacy from adequate and well-controlled investigations demonstrating that the drug product will have the effect it purports or is represented to have in its proposed labeling. Thus, the approved product indication will reflect the endpoint selection in definitive efficacy studies.
Characteristics of adequate and well-controlled studies are described under 21 CFR 314.126. Relevant parts of this regulation state that the purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. Studies are to use a design that permits valid comparison with a control to provide a quantitative assessment of drug effect. The methods of assessment of subjects’ responses are to be well defined and reliable.
Potential endpoints for traditional approval
The choice of endpoints in clinical efficacy trials of prophylactic human papillomavirus (HPV) vaccines will affect the sample sizes, trial designs, duration, resources needed, choice of study populations, and the indication in the vaccine label. In the discussion that follows, endpoints based on virologic, cytologic, and histopathologic outcomes are presented, and arguments both favoring and against those endpoint selections are described. Only endpoints for oncogenic HPV types in the context of cervical abnormalities are considered here.
The presence of an HPV infection in a clinical trial would not be established using classical in vitro cell culture methods. Identification and typing of HPV infections rely on detection of viral DNA using tools of molecular virology, such as polymerase chain reaction (PCR) or DNA hybridization. Serology appears to be less sensitive than molecular techniques in establishing that a new, or incident, infection has occurred, and would likely not be able to distinguish a persistent infection from an infection that has resolved. Both incident and persistent infections (starting during the trial) have been proposed as endpoints in HPV vaccine trials.
Incident HPV infection due to vaccine HPV types
Based on abundant epidemiologic data, infection by an oncogenic HPV type appears to be a necessary step in the pathogenesis of the vast majority of cervical cancers. Specifically, it appears likely that incident HPV infection begins the process of malignant transformation and invasion of cervical tissue. Therefore, prevention of HPV infection may be expected to preclude all subsequent steps in the pathogenesis of cervical cancer.
Studies assessing incident HPV infection as the primary efficacy endpoint may be easier to conduct than studies using other outcome measures. Cases could accrue relatively quickly and be completed within a relatively short period of time, a few years from study initiation. Sample sizes adequate to demonstrate a treatment effect would likely be relatively small (e.g., a few thousand subjects), and may not require the length of follow-up to ascertain endpoints as would be required for endpoints assessing more advanced disease in the pathogenesis of cervical cancer. Definitive efficacy trials for incident HPV infection could be completed within a relatively short time frame, e.g., a few years from study initiation. Monitoring would need to be fairly extensive, e.g., regular Pap smears and HPV testing on all trial participants, plus other interventions such as colposcopy and biopsy, based on a protocol specified algorithm.
From a population perspective, prevention of infection among vaccinated individuals may be expected to result in a decrease in circulating HPV within the larger population. However, this effect is difficult to quantify in the context of an efficacy study.
Prevention of infection can be a difficult endpoint to meet. Typically, the efficacy of vaccines is demonstrated by prevention of disease, as symptomatic disease (or its sequelae) is of greater clinical relevance than is infection, which may be transient and asymptomatic. It is usually symptomatic disease that brings patients to clinicians and trial participants to the attention of clinical investigators. In general, it can be quite difficult to determine whether a vaccine prevents the infection of interest, or whether the vaccine induces an immune response that contains and clears an incipient infection, before disease becomes apparent.
Most incident HPV infections are thought to be asymptomatic and transient without intervention and, therefore, lack clinical relevance for the individual. Thus, a vaccine efficacy estimate for prevention of incident infection could substantially overestimate the protective efficacy for the endpoint of greatest clinical relevance, cervical cancer.
Also, hypothetically, women who develop a poor immune response to an HPV vaccine may be those who are less likely to clear infections spontaneously, and more likely to develop high-grade cervical lesions and cervical cancer. For example, a vaccine that is 90-95% effective in preventing incident infection could be much less effective in preventing high-grade cervical lesions and cancer, if those at greatest risk of progression are over-represented among the 5-10% who would not be protected from infection by the vaccine. If an HPV vaccine proves highly efficacious (>95%) in preventing infection across populations, such a scenario may be less likely.
Another consideration in using incident (or persistent) infection as an efficacy endpoint is the reliability of detection of type-specific HPV infection, both at study entry and throughout the trial. Detection of incident or persistent HPV infection relies on detection of DNA from cervical samples or smears. These samples obtain superficial cervical cells more so than basal layer cells. (This type of HPV testing should be distinguished from testing of biopsy samples, e.g., with in situ hybridization of actual lesions). Thus, it may not always be possible to distinguish a new infection from a recurrence or reactivation of a previously latent infection. Assuming a sensitive assay, productive HPV infections (i.e., infection resulting in shedding of infectious viral particles) may be detected readily, but there is uncertainty about detecting “latent” infections, which would be expected to exist predominantly in basal layer cells of the cervical epithelium.
In a randomized study design, inability to detect the presence of HPV infection at study entry would likely be evenly distributed among groups. While this type of uncertainty about the case definition would not result in systematic bias of measures of efficacy, it would result in less case specificity and may result in a less precise estimate of efficacy. Moreover, if an incident infection in a previously uninfected person achieves latency and integration prior to the next scheduled visit, it might be falsely concluded that no infection occurred. Additionally, it is plausible that a vaccine induced immune response might impair detection of HPV DNA, possibly by facilitating clearance of virus from the more superficial epithelium, while infection and integration of cells in the deeper epithelial layers, especially the basal layer, persists.
The benefits of vaccination to prevent asymptomatic HPV infections may not be viewed favorably when compared to risks of adverse events related to vaccination. This risk-to-benefit assessment would more likely favor vaccination if clear evidence for prevention of high-grade cervical lesions were demonstrated.
Finally, although virologic endpoint studies may allow for demonstration of efficacy using relatively small sample sizes, large randomized datasets are preferred to evaluate safety of HPV vaccines. The bulk of safety data supporting licensure of vaccines is usually obtained in trials designed to demonstrate efficacy. If virologic endpoints are chosen based largely on feasibility considerations, it may be necessary to conduct additional randomized trials in order to closely monitor a large cohort of individuals for safety outcomes.
Persistent HPV infection by oncogenic HPV types
Persistent HPV infection can be defined by the presence of type-specific HPV DNA on repeated visits over some period of time. In one large study, detection of HPV type 16 DNA in the last 2 Pap smears before a diagnosis of carcinoma in situ (CIS) excluding smears taken less than 1 year before diagnosis, was found to have a higher odds ratio for association with CIS than was a single finding of HPV DNA (Ylitalo N et al., Cancer Res, 2000). In another study, the relative risk for developing squamous intraepithelial lesions (29 of 31 were low grade) was 37 (95% CI: 14.6-95) for women with the same high-risk type HPV detected at two consecutive visits (6 months apart) compared to women who were HPV negative at one or both visits (Ho GYF et al., 1998).
The optimal interval after which an HPV infection would be considered persistent is not readily apparent. Estimates of the median duration of HPV type 16 infection vary from 8 to 12 months (Ho GYF et al., 1998, Franco EL et al., 1999, Woodman CB, et al., 2001). Thus, study designs in which HPV testing is performed every 4-6 months could conclude that an infection is persistent in cases where viral clearance proceeds normally within a typical duration of infection.
Reservations regarding use of incident HPV infection as an endpoint, as discussed above, also apply to persistent infection. Like incident infection, most persistent infections are thought to be asymptomatic, and, therefore, lack clear clinical relevance for the individual. Clinical trials using only virologic endpoints, ignoring cervical pathology, could significantly overestimate the benefit from vaccination for prevention of cervical cancer. Until an efficacy study using clinical endpoints is conducted that clearly validates virologic endpoints as quantitatively predictive of clinical outcomes of interest with HPV vaccine use, the value of virologic endpoints used without cervical pathology will remain uncertain.
If virologic endpoints are not judged to be adequate for demonstrating efficacy in preventing cervical cancer, it is possible that incident or persistent infection might be suitable surrogate endpoints to support accelerated approval, as described in the FDA regulations. Accelerated approval is discussed later in this document.
Endpoints based on cytology
LSIL and/or ASC, or worse, in association with oncogenic HPV types
Low-grade squamous intraepithelial lesion (LSIL) as discussed in this section, and atypical squamous cells (ASC) are cytologic terms used in the interpretation of Pap smear results. Management of such cytology findings may vary. Workup by immediate colposcopy may occur. However, depending on clinical factors such as availability for follow-up and immune status, clinicians may elect to follow-up such cytologic findings with another Pap smear without immediate colposcopy. When incident or persistent LSIL leads to colposcopy and biopsy, abnormal findings could be reflected in a pathologic diagnosis, such as cervical intraepithelial neoplasia (CIN), as discussed in several sections below.
It may be argued that prevention of LSIL or ASC, or prevention of persistent LSIL would translate into fewer repeat Pap smears, colposcopies and biopsies, and thus would provide evidence of clinical benefit. However, there must be histologic evidence (e.g., CIN 1 on biopsy) in order to initiate treatment. In the US, a finding of LSIL cytology by itself is an insufficient basis to treat. Thus, prevention of the pathologic diagnosis (by histology) would more clearly indicate clinical benefit.
Endpoints based on histology
CIN 1 histology, adenocarcinoma in situ (AIS) of the cervix, or worse, in association with oncogenic HPV types
Cervical intraepithelial neoplasia (CIN) is a pathologic diagnosis based on tissue obtained at biopsy, e.g., after a Pap screening test finding of ASC or LSIL. CIN 1 histology is considered a low-grade lesion. The histology is characterized by a finding of undifferentiated cells in the lower third of the cervical epithelium. A pathologic diagnosis of CIN I, or worse, by biopsy is considered more definitive than a cytologic finding of LSIL with regard to therapeutic decisions. Biopsy specimens would include the basal epithelium, thus possibly enabling identification of latent or otherwise inapparent HPV infection. The actual lesions can be evaluated for HPV type by in situ hybridization.
Because a diagnosis of CIN 1 is based on tissue samples, prevention of CIN 1 or worse would directly reflect prevention of a procedure (biopsy).
In a recent study (ALTS), 26% (298/1149) of subjects with ASC (at entry) who were randomized to immediate colposcopy had CIN (majority are CIN 1), or worse, at biopsy (Solomon D et al., 2001). In addition, studies have found that 52 to 85% of women with LSIL cytology have CIN (majority are CIN 1) or worse on biopsy [Lonky NM e al., 1999; Jones BA, 2000].
Similar to LSIL, about 50% of CIN 1 regressed to normal (Östör AG, 1993). (See Natural History section of the FDA HPV Vaccine Background document for more details.) The risk of CIN 1 progressing to cancer over a period of months or even a few years is thought to be low, at least in those subjects with adequate follow-up [ASCCP (1), 2001; Östör AG, 1993]. Thus, an efficacy estimate for prevention of CIN 1 could substantially overestimate the efficacy in preventing cervical cancer, although the magnitude of an overestimate may be diminished if the efficacy in preventing CIN 1 is high.
Also of interest here, in at least 2 longitudinal studies, some women with normal cytology at baseline had a diagnosis of CIN2/3 (histology) identified on initial workup for an abnormal Pap smear during the study (Koutsky LA et al., 1992; Woodman CD et al., 2001).
If licensure of HPV vaccines were to be based on prevention of predominantly CIN 1, the vaccine indication in the label would reflect that the vaccine prevents CIN 1, not cervical cancer. Additional efficacy studies would be required post-licensure to justify extending the labeled indication to include prevention of cervical cancer.
CIN 2/3 histology, adenocarcinoma in situ (AIS) of the cervix, or worse, in association with oncogenic HPV types
Most of the endpoints in this category would be CIN 2 or 3. CIN 2 is defined by moderate dysplasia. CIN 3 includes both severe dysplasia and carcinoma in situ. Both CIN 2 and 3 are considered high-grade cervical lesions. In the US, little distinction is made between CIN 2 and CIN 3 in terms of medical management. Thus, it is reasonable to consider CIN 2/3, AIS, or worse as a single entity for the purpose of selection of efficacy endpoints for HPV vaccine trials. If efficacy trials using cervical cancer as the endpoint cannot be conducted, prevention of CIN 2/3, AIS, or worse will most closely approximate the preventive efficacy of HPV vaccines for cervical cancer.
As discussed under the CIN 1 or worse endpoint section, a pathologic diagnosis based on tissue is needed for therapeutic decisions. Prevention of CIN 2/3 would translate into prevention of both the diagnostic biopsy, and a subsequent therapy (excisional or ablative procedure, as appropriate). Thus, in preventing CIN 2/3, substantial clinical benefit will have been realized.
It has been argued that studies examining CIN 2/3 as the primary efficacy endpoint could be prohibitively resource intensive, and of long duration. Concerns expressed regarding use of CIN 2/3 as a primary efficacy endpoint have focused on the following areas:
1. The length of trial considerations as well as sample size projections have been cited as a problem, although little specific information has been presented or published in this regard (WHO meeting, Geneva, Switzerland 1999).
2. Large preventive vaccine efficacy trials, e.g., 10,000 to 40,000 enrollees, are not unusual. However, the type of follow-up (i.e., multiple clinical examinations and laboratory testing) makes this sort of trial more resource intensive and complex than typical preventive vaccine efficacy trials, although similar to virologic endpoint trials with regard to resources per subject per year.
3. In a trial of subjects being followed, e.g., at 4, 6, or 12-month intervals, a certain percentage of incident cervical dysplasia would need to be CIN 2/3 at initial work-up, in order to accrue sufficient cases of CIN 2/3 to demonstrate efficacy. This may be the case whether or not CIN 1 is treated during a trial.
It should be noted that a certain proportion of women with ASC, LSIL and atypical glandular cells (AGC) cytology will have HSIL/CIN 2/3 upon initial work-up. In fact, work-up of such low-grade lesions with colposcopy and biopsy could generate most of the CIN 2/3, AIS, or worse diagnoses in an efficacy trial (Kinney WK et al., 1998; Lonky NM et al., 1999; Woodman CB et al., 2001). Across studies, the proportion of women with CIN 2/3 or worse following the work-up for ASCUS (ASC) has ranged from about 6% to 11% (Solomon D et al., 2001). For LSIL, the proportion with CIN 2/3 or worse at work-up has usually ranged from about 16% to 28% [ASCCP (1) 2001]. However, several European studies have reported rates as high as 50-70%. For AGUS (AGC), the proportion with CIN 2/3 or worse at work-up has usually ranged from about 9-13%, with a special concern about the percent of frank cancer (as discussed in the other FDA document).
The estimate of the size/duration of a preventive HPV vaccine efficacy trial with a CIN 2/3, AIS, or worse endpoint would come from a prospective cohort of closely monitored subjects who have normal cytology and negative HPV testing results at baseline. Data from one such longitudinal study was recently published (Woodman C et al., 2001, included with FDA briefing materials). In this prospective study conducted in the UK, 1075 women with normal Pap smears and who were negative for HPV at study entry, were followed for a median of 26 months. A diagnosis of CIN 2 or 3 was established for 28 women, 20 of whom were diagnosed with CIN 2 or 3 during work-up of the first episode of abnormal cytology. Median time to diagnosis of CIN 2/3 was 36 months from study entry.
If one assumes the following parameters, approximately 12,000 women would need to be enrolled:
A trial with 1:1 randomization, HPV 16 and 18 infection rate similar to the Woodman et al., article, a vaccine efficacy of ³ 80%, trial duration of 3 1/2 years (mean follow-up 3 years), 80% power, 20% loss to follow-up, and about 50% of incident CIN 2/3 cases attributed to vaccine types (HPV type 16 or 18).
If preventive efficacy trials using cervical cancer as the outcome are deemed not feasible or not appropriate, then endpoints based on high-grade CIN pathologic criteria, in the context of HPV infection, appear to be the most clinically relevant and most accurate in predicting and quantifying the preventive efficacy of HPV vaccines for cervical cancer. Should efficacy of an HPV vaccine in preventing high-grade cervical lesions be demonstrated, a labeled indication for prevention of cervical cancer may be considered.
Cervical cancer (invasive)
Prevention of cervical cancer would be the most clinically relevant endpoint for a preventive HPV vaccine comprising oncogenic types. However, there appears to be significant feasibility issues for conducting a vaccine study using cervical cancer as the endpoint. Standard of care in the US dictates that women enrolled in HPV vaccine trials would be followed closely by means of Pap screening and other interventions, as appropriate. Given the relatively protracted duration of carcinogenesis following HPV infection (median time from HPV infection to carcinoma in situ has been estimated to be 7-12 years) (Ylitalo N et al., Cancer Res 2000), and the relatively low frequency of cervical cancer in the US due to screening and early treatment, clinical studies using cervical cancer as an endpoint could require a prolonged duration of follow-up to identify sufficient cases to establish efficacy.
The possibility of conducting a long-term, e.g., up to 20 year, population based trial to evaluate the impact of vaccination on ICC (invasive cervical cancer) [with or without CIN 3] in Nordic countries and Estonia has been discussed in the literature. The proposal involved use of cancer registry follow-up. For example, Finland has a country-wide cancer program where practically all invasive cancer cases (>95% histologically confirmed diagnoses) are captured; in addition, CIN 3 and adenocarcinoma in situ are captured (Lehtinen M et al., 2000).
It might be considered feasible to conduct HPV vaccine studies using cervical cancer as an endpoint in areas of the world where cervical cancer rates are high, and screening and treatment are not effectively employed. However, in the context of a clinical trial, some would consider it unethical not to provide effective screening and treatment to all participants, even if that level of medical care would not otherwise be available. If effective screening and treatment were made available, then the rates of cervical cancer would be expected to fall, and advantages of conducting trials in those high incidence areas might no longer exist.
Another complex issue for a cervical cancer trial, given the size of such a trial, could be screening for HPV and exclusion at baseline. Without screening and exclusion at baseline, pre-existing HPV infection may substantially dilute vaccine efficacy estimates, as well as increase sample size. The same consideration (although logistically more feasible) applies to the decision of whether or not to HPV test/type the cervical cancer specimens.
Other considerations affecting the selection of endpoints
It should not be assumed that efficacy trials with endpoints such as CIN 2/3 must be conducted in developing countries. HPV infection annual incidence rates that equal or exceed ~ 3% for HPV Type 16 and ~2% for HPV Type 18 have been documented in cohorts in developed countries (Woodman CB et al., 2001; Ho GYF et al., 1998; Thomas KK et al., 2000). If HPV infection is linked to the subsequent development of CIN 2/3 (or worse), then these cohorts would appear to be relatively high-risk populations for the development of high-grade cervical lesions.
The public health community may have difficulty assessing the value of wide implementation (for the US and elsewhere) of an HPV vaccine if the approval is based on endpoints associated with asymptomatic infections, when the effect on the medical conditions of interest, high-grade dysplasia and/or cervical cancer, has not been demonstrated in a well-controlled trial.
When multiple serotypes, etc., of an infectious agent cause disease, the primary endpoint in vaccine efficacy trials has been prevention of disease caused specifically by the ones represented in the vaccine (e.g., pneumococcal conjugate vaccine comprising 7 of the most common serotypes). Cervical cancer has been associated with multiple oncogenic HPV types, of which HPV type 16 is the most common, found in approximately 50% of cervical cancers. Limiting the primary endpoint to HPV types represented in the vaccine will likely result in a higher vaccine efficacy estimate than if the endpoint reflected disease caused by all HPV types. However, prevention of all cervical cancer associated with HPV is the ultimate goal of an HPV vaccine. Therefore, it will also be important in HPV vaccine trials to conduct pre-specified secondary analyses to assess efficacy of the vaccine for the chosen endpoints (e.g., all CIN 2/3), regardless of the HPV type implicated. Such secondary analyses have the potential to address questions that can be important to the overall risk-benefit assessment, such as “replacement” disease caused by non-vaccine types or other infectious diseases.
Another consideration is that adenocarcinoma accounts for an increasing proportion of cervical cancer in developed countries. HPV Type 18 is the type most commonly associated with cervical adenocarcinoma (Smith HO et al., 2000). Type 18 infections may be fundamentally different from Type 16 infections. Trials using an endpoint other than cervical cancer may not provide sufficient data to make conclusions about the protective efficacy of HPV Type 18 vaccines.
It may not be possible to conduct additional placebo-controlled clinical endpoint studies after licensure of an HPV vaccine, regardless of the efficacy endpoint that provided the basis of licensure. Furthermore, non-inferiority studies comparing a licensed HPV vaccine to another candidate HPV vaccine, using clinical endpoints would need to be larger and even more resource intensive than placebo-controlled studies. Thus, the opportunity to conduct and complete a vaccine study using prevention of high-grade cervical lesions as the primary efficacy outcome, as compared to placebo, may be lost with the licensure of the first HPV vaccine.
[21 CFR 601 Subpart E: Accelerated Approval of New Biologic Products for Serious or Life-Threatening Illnesses]. This subpart of the regulations applies to certain biological products that have been studied for the treatment of serious or life-threatening illnesses, and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy). “FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that a biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity” (Sec. 601.41).
The accelerated approval regulations were intended to make available promising therapies while the definitive confirmatory efficacy studies were completed. Products approved under the accelerated approval regulations must be studied further, to verify and describe clinical benefit of the product, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.
Confirmatory post-marketing studies would usually be studies already well underway at the time of accelerated approval; these studies must be carried out with due diligence. Safety of the product will have been demonstrated at the time of accelerated approval. Should the confirmatory studies fail to demonstrate efficacy for clinical endpoints, the product may be withdrawn from the market.
The accelerated approval regulations originated in the setting of rising mortality due to acquired immunodeficiency syndrome (AIDS), prior to availability of highly active antiretroviral agents. The original, and current, intent of accelerated approval regulations is to serve the best interests of the public. Drugs for treatment of HIV infections, drugs and biologics for the treatment of cancer, and other therapeutic products have been approved under accelerated approval. However, the accelerated approval provisions have not previously been invoked for licensure of a prophylactic vaccine.
Accelerated approval and HPV vaccines
Cervical cancer is clearly a serious and life-threatening medical condition. The time from incident infection by oncogenic HPV types to high-grade neoplasia or cancer may be years, and the event rate in a population that has normal cytology and negative HPV status at baseline could be quite low. It has been suggested that studies using CIN 2 and CIN 3 as primary efficacy endpoints could also be resource intensive. Nevertheless, such trials may be feasible, as discussed earlier.
Interest in surrogate endpoints and accelerated approval for HPV vaccines is understandable given the duration of trials that may be required to document unequivocal histologic evidence of high-grade cervical dysplasia or cancer. However, the appropriateness of accelerated approval regulations to prophylactic HPV vaccines is open to interpretation. Available options for preventing cervical cancer include cytologic screening with appropriate interventions, e.g., colposcopy, biopsies, and excisional or ablative procedures as indicated. It may be argued that these prevention modalities are both effective and widely available in the US. It is also expected that continued screening will be necessary, even if HPV vaccines are effective and become available, in order to prevent cervical lesions caused by HPV types not included in the vaccines. On the other hand, a reduction in the number of surgical interventions could be considered a meaningful therapeutic benefit to patients over existing treatments. Of note, cost-effectiveness cannot be used as the basis for FDA regulatory decisions.
To date, the intended populations for products approved under accelerated approval have been limited to those groups of individuals affected by the severe or life-threatening condition in question. In the case of HPV vaccines, all healthy adolescents and adults could comprise the intended target population. Public health decisions regarding such wide implementation of an HPV vaccine following accelerated approval based on a surrogate endpoint rather than the medical conditions of interest, high-grade dysplasia and/or cervical cancer could be particularly difficult, as was discussed above in the context of traditional approvals based on virologic endpoints or low grade lesions
Should accelerated approval regulations be judged an acceptable pathway for the licensure of HPV vaccines, surrogate and confirmatory endpoints will need to be identified.
Surrogate Endpoints for Accelerated Approvals
FDA regulations state that the surrogate must be “reasonably likely”, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict benefit for the serious or life-threatening condition of interest. Thus, the strength of evidence demonstrating that a surrogate predicts benefit in life-threatening conditions can be broadly interpreted. Arguments can be made that incident HPV infection, persistent HPV infection, LSIL cytology associated with HPV infection, and CIN 1 associated with HPV infection are reasonably likely to predict benefit.
For reasons discussed above, the most informative of these candidate surrogates may be CIN 1 associated with oncogenic HPV.
Confirmatory Trials for Accelerated Approvals
One of the necessary conditions for accelerated approval is that the indication be for treatment or prevention of a serious or life-threatening illness. The confirmatory trial should validate that the surrogate endpoint predicts the outcome of interest. However, because the current practice of screening and treatment of pre-cancerous cervical lesions is largely effective in preventing cervical cancer in the US, the most appropriate confirmatory endpoints would be those most proximal to the endpoint of cervical cancer. It appears that an endpoint combining all cases of CIN 2, CIN 3, AIS, and those cases of cervical cancer not detected through screening and treatment combined is the most appropriate confirmatory endpoint, if the accelerated approval path is followed.
Once a product becomes available through accelerated approval, it may be quite difficult to conduct confirmatory studies because of widespread availability of the product. Sponsors might propose conducting confirmatory studies in countries where the product is not yet approved or available. However, as would be the case following a traditional approval, it may be problematic in the post-licensure setting to conduct trials in which subjects would be randomized to a placebo, even if the product is not otherwise available. Therefore, if a path to accelerated approval is pursued, the confirmatory trials should be fully accrued and well underway at the time of an accelerated approval in order to assure that the confirmatory trials would yield a definitive result. An efficient approach to past accelerated approvals has been to embed the surrogate endpoint study within a confirmatory endpoint study. Given the long duration of follow-up that may be required to accrue sufficient cases of high-grade lesions, it is also unclear whether completion of the confirmatory trials would be feasible.
What if Gardasil has been pushed to make money out of patients? What if Gardasil would be harmful?
Why inject young girls and boys with a dangerous and life threatening vaccine when the herb Pau d’ Arco has been proven to both prevent and cure HPV?
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